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Sodium metabisulfite (SMB) is commonly utilized in food to preserve freshness by acting as an antioxidant and antimicrobial agent. However, when SMB interacts with water in biological systems, it produces harmful byproducts such as sulfite and sulfur dioxide. These byproducts induce cellular stress and programmed cell death, known as apoptosis, by triggering excessive production of reactive oxygen species. Our study demonstrates that supplementation with nicotinamide mononucleotide (NMN) effectively mitigates the damage caused by SMB to porcine oocytes during their cultivation in laboratory conditions. NMN supplementation not only preserves the oocytes' ability to undergo meiosis with intact spindle and chromosome structures but also enhances their capacity for fertilization by promoting the activity of cortical granule component protease. The protective effects of NMN on porcine oocytes exposed to SMB involve the restoration of mitochondrial function and the reduction of accumulated reactive oxygen species, leading to inhibition of apoptosis. These findings suggest that excessive SMB will impair mitochondrial function in porcine oocytes, which in turn causes oxidative stress and apoptosis, and impedes maturation of porcine oocytes and development of post-fertilised embryos, and that supplementation with NMN is a promising strategy to protect oocytes from the deleterious effects of SMB exposure., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Kidney stone formation is a common disease that causes a significant threat to human health. The crystallization mechanism of calcium oxalate, the most common type of kidney stone, has been extensively researched, yet the damaging effects and mechanisms of calcium oxalate crystals on renal tubular epithelial cells remain incompletely elucidated. Regulated mitochondrial dynamics is essential for eukaryotic cells, but its role in the occurrence and progression of calcium oxalate (CaOx) nephrolithiasis is not yet understood., Methods: An animal model of calcium oxalate-related nephrolithiasis was established in adult male Sprague‒Dawley (SD) rats by continuously administering drinking water containing 1% ethylene glycol for 28 days. The impact of calcium oxalate crystals on mitochondrial dynamics and apoptosis in renal tubular epithelial cells was investigated using HK2 cells in vitro. Blood samples and bilateral kidney tissues were collected for histopathological evaluation and processed for tissue injury, inflammation, fibrosis, oxidative stress detection, and mitochondrial dynamics parameter analysis., Results: Calcium oxalate crystals caused higher levels of mitochondrial fission and apoptosis in renal tubular epithelial cells both in vivo and in vitro. Administration of a PPARγ agonist significantly alleviated mitochondrial fission and apoptosis in renal tubular epithelial cells, and improved renal function, accompanied by reduced levels of oxidative stress, increased antioxidant enzyme expression, alleviation of inflammation, and reduced fibrosis in vivo., Conclusion: Our results indicated that increased mitochondrial fission in renal tubular epithelial cells is a critical component of kidney injury caused by calcium oxalate stones, leading to the accumulation of reactive oxygen species within the tissue and the subsequent initiation of apoptosis. Regulating mitochondrial dynamics represents a promising approach for calcium oxalate nephrolithiasis., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Liu et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

As a prevalent neurodegenerative disorder, Parkinson's disease is associated with oxidative stress. Our recent investigations revealed that reactive oxygen species (ROS) and PD-toxins like 6-hydroxydopamine (6-OHDA) can induce neuronal apoptosis through over-activation of Akt signaling. Chlorogenic acid (CGA), a natural acid phenol abundant in the human diet, is well-documented for its ability to mitigate intracellular ROS. In this study, we utilized CGA to treat experimental models of PD both in vitro and in vivo. Our study results demonstrated that SH-SY5Y and primary neurons exhibited cell apoptosis in response to 6-OHDA. Pretreatment with CGA significantly attenuated PD toxins-induced large amount of ROS, inhibiting Erk1/2 activation, preventing Akt inhibition, and hindering neuronal cell death. Combining the Erk1/2 inhibitor U0126 with CGA could reverse 6-OHDA-induced Akt inhibition, ROS, and apoptosis in the cells. Crucially, the Akt activator SC79 and ROS scavenger NAC both could eliminate excessive ROS via Akt and Erk1/2 signaling pathways, and CGA further potentiated these effects in PD models. Behavioral experiments revealed that CGA could alleviate gait abnormalities in PD model mice. The neuroprotective effects have been demonstrated in several endocrine regions and in the substantia nigra tissue, which shows the positive tyrosine hydroxylase (TH). Overall, our results suggest that CGA prevents the activation of Erk1/2 and inactivation of Akt by removing excess ROS in PD models. These findings propose a potential strategy for mitigating neuronal degeneration in Parkinson's disease by modulating the Akt/Erk1/2 signaling pathway through the administration of CGA and/or the use of antioxidants to alleviate oxidative stress., Competing Interests: Declaration of competing interest The authors declare that they have no conflicts of interest with the contents of this article., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Lipopolysaccharide-induced TNFα factor (LITAF) is an important transcription factor which activates the transcription of TNFα and regulates cell apoptosis and inflammatory response. In the present study, a LITAF gene homologue was identified in zebrafish (Danio rerio) and was shown to be well conserved in the protein sequence, genomic organization and synteny with human LITAF. DrLITAF was constitutively expressed in tissues, with the highest expression detected in the gills. Its expression could be modulated by LPS, poly(I:C), and infection with Edwardsiella tarda, Aeromonus hydrophila and septicemia viremia of carp virus (SVCV). DrLITAF, when overexpressed, was shown to be located on the cellular membrane and nuclear membrane of HEK293T and ZF4 cells and was associated with the endoplasmic reticulum. Stimulation with LPS resulted in rapid translocation of DrLITAF into the nucleus. In addition, DrLITAF was able to induce cell apoptosis and the expression of caspase 3. The results demonstrate that DrLITAF is involved in the immune defence against bacterial and viral infection and plays a role in regulating inflammation and apoptosis., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Phenotypes of haploid embryonic stem cells (haESCs) are dominant for recessive traits in mice. However, one major obstacle to their use is self-diploidization in daily culture. Although haESCs maintain haploidy well by deleting p53, whether they can sustain haploidy in differentiated status and the mechanism behind it remain unknown. To address this, we induced p53-deficient haESCs into multiple differentiated lineages maintain haploid status in vitro. Haploid cells also remained in chimeric embryos and teratomas arising from p53-null haESCs. Transcriptome analysis revealed that apoptosis genes were downregulated in p53-null haESCs compared with that in wild-type haESCs. Finally, we knocked out p73, another apoptosis-related gene, and observed stabilization of haploidy in haESCs. These results indicated that the main mechanism of diploidization was apoptosis-related gene-triggered cell death in haploid cell cultures. Thus, we can derive haploid somatic cells by manipulating the apoptosis gene, facilitating genetic screens of lineage-specific development., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)

Aim: The study aimed to investigate the effects of DNA repair proteins on cell apoptosis in human DPSCs during inflammation., Methods: Lipopolysaccharide (LPS) was used to stimulate inflammation in dental pulp in vivo and in vitro. We identified the activation of DSB response and DNA repair proteins in inflamed pulp tissue and in LPS-treated human DPSCs. Then we transfected the cells with Ku70 (a key protein involved in NHEJ) siRNA and detected the expression changes of γ-H2A.X, DNA repair proteins and cell apoptosis., Results: Immunohistochemical staining showed that at 4 and 6 days of pulpitis the expression of Ku70 and γ-H2A.X significantly increased. The levels of γ-H2A.X, Ku70, Xrcc4, and Rad51 increased considerably in the LPS-treated DPSCs. Furthermore, decreased expression of Ku70 could increase the number of γ-H2A.X foci, apoptotic cells and reduce cell viability in DPSCs., Conclusions: The results indicate that NHEJ pathway was the main mechanism involved in DNA damage response induced by repeated LPS stimulation in DPSCs. Meanwhile, the findings suggested that Ku70 serves importantly in the apoptosis of DPSCs in the inflammatory environment.

Epithelial ovarian cancer (EOC) is one of the most prevalent gynaecological cancers. Euxanthone, an active ingredient of the medicinal plant Polygala caudata, exhibits a selective cytotoxic effect in tumour cells. The present study was aimed to determine whether euxanthone could suppress ovarian tumour growth, and to study the relevant mechanism. Two EOC cell lines, SKOV3 and A2780, were used as the in vitro model and treated with euxanthone. Cell viability and apoptosis were assayed using Cell Counting Kit-8 (CCK-8) and Annexin-V FITC/PI staining, respectively. Commercially available kits were used to measure the glucose consumption, lactate production, and intracellular ATP levels. Western blots assay was conducted to examine the level of apoptotic markers. To examine the roles of HK2 and STAT3 in the anti-tumour effect of euxanthone, cells were transfected with vectors overexpressing HK2 or STAT3, and assayed as above. Finally, SKOV3 cells were injected to mice models to appreciate the anti-neoplastic effect of euxanthone in vivo. We found that euxanthone impaired the cell viability and induced apoptosis via the intrinsic pathway in a concentration-dependent fashion in both SKOV3 and A2780 cells. Euxanthone also caused inhibition of glycolysis. Apoptosis and glycolysis inhibition was mediated by the downregulation of HK2, which in turn was a result of STAT3 inactivation. In vivo experiments also supported that euxanthone could exert anti-cancer activities without general toxicity. In conclusion, euxanthone triggered mitochondrial apoptosis and inhibited glycolysis in EOC cells., Significance of the Study: Euxanthone triggered mitochondrial apoptosis and inhibited glycolysis in EOC cells. Our findings provide preliminary experimental data that support further studies on the potential therapeutic role of euxanthone in ovarian cancer., (© 2018 John Wiley & Sons, Ltd.)

We hypothesized that SIRT1 downregulation in osteoblasts induced by wear particles was one of the reasons for particle-induced osteolysis (PIO) in total joint arthroplasty failure. In the present study, the expression of SIRT1 was examined in osteoblasts treated with TiAl6V4 particles (TiPs) and CoCrMo particles (CoPs) from materials used in prosthetics and specimens from PIO animal models. To address whether SIRT1 downregulation triggers inflammatory responses and apoptosis in osteoblasts, the effect of a SIRT1 activator, resveratrol on the expression of inflammatory cytokines and apoptosis in particle-treated osteoblasts was tested. The results demonstrated that SIRT1 expression was significantly downregulated in particle-treated osteoblasts and PIO animal models. Both pharmacological activation and overexpression of SIRT1 dramatically reduced the particle-induced expression of inflammatory cytokines and osteoblast apoptosis through NF-κB and p53 signaling, respectively. Furthermore, in PIO animal models, resveratrol significantly reduced the severity of osteolysis. Collectively, the results of the present study indicated that SIRT1 plays a vital role in the pathogenesis of aseptic loosening, and further treatment targeted at SIRT1 possibly lead to novel approaches for prevention of aseptic prosthesis loosening., Statement of Significance: Aseptic loosening is the most common cause of total hip arthroplasty (THA) and total knee arthroplasty (TKA) failure and revision surgery. However, there is still no effective therapeutic target in the clinical treatment. Besides, the underlying mechanism of aseptic loosening is largely unknown. The result of our study indicated that SIRT1 has the ability to effectively regulate the wear particle-induced inflammatory responses, apoptosis, osteolysis in particle-stimulated osteoblasts and particle-induced osteolysis animal models. Our study provides a potential target for the prevention and treatment of aseptic loosening and further investigated the underlying mechanism of aseptic loosening, which may make contribution to decrease the incidence of THA and TKA failure in the clinical practice., (Copyright © 2016 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.)

Lipoteichoic acid (LTA) is a major constituent of the cell wall of Gram-positive bacteria. The structure and immunomodulation of LTA vary greatly between different species. LTA from Lactobacillus plantarum has been shown to exert anti-pathogenic effects. Vibrio anguillarum is a major causative agent of vibriosis, one of the most prevalent fish diseases. The purpose of this study was to examine the effects of L. plantarum LTA on V. anguillarum growth, adhesion, and induced inflammation and apoptosis in intestinal epithelial cells of silvery pomfret (Pampus argenteus). Our results showed that L. plantarum LTA was unable to inhibit V. anguillarum growth; however, it significantly inhibited adhesion of V. anguillarum. It also showed significant inhibitory effects on EHEC-induced inflammation and apoptosis by modulating the expression of NF-κB (nuclear factor kappa B), IκB (inhibitor of NF-κB), Bcl2 (B-cell leukemia/lymphoma-2), BAX (Bcl-2-associated X protein), IL-8 (interleukin 8) and TNF-α (tumor necrosis factor-α), and via inhibition of caspase-9 and caspase-3 activation. These data extend our understanding of the beneficial effects of L. plantarum LTA, which is related to the inhibition of V. anguillarum, and suggest that L. plantarum LTA has potential as a new therapeutic agent against V. anguillarum-caused vibriosis in fish., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

The cell wall lipids phthiocerol dimycocerosates (PDIMs) and its structurally-related compound, phenolic glycolipids (PGLs) are major virulence factors of mycobacterium, as shown by the reduced growth of PDIMs/PGLs deficient mutants in various animal models. PDIMs/PGLs play active roles in modulating host immune responses. However, the cellular and molecular mechanisms of how PDIMs/PGLs deficient mutant was eliminated in vivo are still elusive. Our aim was to investigate what host immune responses have effect on mycobacterium elimination in vivo. Using microarray, we find PDIMs/PGLs modulate divergent host responses, including chemotaxis and focal adhesion's downstream pathway and apoptosis. We examine these two host responses by Diff-Quik stain, coupled with transmission electron microscopy and TUNEL stain respectively. The ultrastructure observation showed that eosinophils appeared in WT-infected zebrafish at day 1, however eosinophils arrived was delayed to day 7 in PDIMs/PGLs-deficient mutant-infected animals. More intriguingly, apoptosis was markedly increased in PDIMs/PGLs-mutant infected zebrafish at day 1 after infection, compared to WT-infected fishes at this time. However, apoptosis trend was fully reversed by day 7, with increased apoptosis were detected in WT-infected zebrafish compared with the PDIMs/PGLs-deficient mutant, especially more apoptosis within the granuloma. This study shows that the anti-apoptotic effects of PDIMs/PGLs and the recruitment of eosinophils in tissue during the early infection in zebrafish might promote bacterium growth in vivo., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Purpose: Dragon's blood (DB), a Chinese traditional herb, was shown to have certain protective effects on radiation-induced bone marrow injury due to the presence of several phenolic compounds. The 50% ethanol extracts (DBE) were separated from DB by the methods of alcohol extracting-water precipitating. The protective effects of DBE on hematopoiesis were studied, particularly on megakaryocytes., Materials and Methods: In this study, we investigated the in vivo radioprotective effects of DBE on hematopoiesis and pathological changes using an irradiated-mouse model. Moreover, the protective effects and potential molecular mechanisms of DBE on megakaryocytopoiesis in vitro were explored in GM-CSF depletion-induced Mo7e cell model., Results: DBE significantly promoted the recovery of peripheral blood cells in irradiated mice. Histology bone marrow confirmed the protective effect of DBE, as shown by an increased number of hematopoietic cells and a reduction of apoptosis. In a megakaryocytic apoptotic model, DBE (50 µg/mL) markedly alleviated GM-CSF withdrawal-induced apoptosis and cell-cycle arrest of Mo7e cells. DBE (50 µg/mL) also significantly decreased the ratio of Bax to Bcl-2 expression, inhibited the active caspase-3 expression. In addition, DBE could induce ERK1/2 phosphorylation in GM-CSF-depleted Mo7e cell, but not Akt., Conclusions: Our data demonstrated that DBE could effectively accelerate the recovery of peripheral blood cells, especially platelet. DBE attenuated cell apoptosis and cell cycle arrest through the decrease of Bax/Bcl-2 ratio and the reduction of active caspase-3 expression. The effect of DBE on Mo7e cells survival and proliferation is likely associated with the activation of ERK, but not Akt., (Copyright © 2015 Associazione Italiana di Fisica Medica. Published by Elsevier Ltd. All rights reserved.)

Macrophages, a type of immune cell, are the precursors of osteoclasts, and have important roles in bone remodeling and the immune system. In the present study, the RAW264.7 cell line was used as a macrophage model in order to study the macrophage changes during osteoclastogenesis. Receptor activator of nuclear factor κB ligand (RANKL) and macrophage colony‑stimulating factor (M‑CSF) induce the formation of osteoclasts from several precursor cells. Observation of RAW264.7 macrophage osteoclastogenesis under the induction of RANKL and M‑CSF revealed that except the few RAW264.7 macrophages that were differentiated into osteoclasts, almost all undifferentiated RAW264.7 macrophages underwent apoptosis. BRL‑3A cells have no differentiation ability, and RANKL and M‑CSF treatments did not induce BRL‑3A cell apoptosis. When osteoprotegerin (OPG) was used to completely inhibit the differentiation of RAW264.7 macrophages to osteoclasts, apoptosis did not occur amongst the RAW264.7 macrophages despite the action of RANKL and M‑CSF. Rac1, RhoA and RhoV are apoptosis‑associated genes in the Rho guanosine triphosphate (GTP)ase family. Their expression levels were detected using quantitative polymerase chain reaction (qPCR). During the process of osteoclast differentiation, the mRNA expression of RhoV was significantly upregulated, while apoptosis occurred in a large proportion of macrophages. However, when macrophage apoptosis was inhibited by OPG, RhoV expression was significantly downregulated. Conversely, Rac1 and RhoA expression did not vary in correspondence with the apoptotic rate of the RAW264.7 macrophages. In conclusion, differentiation of RAW264.7 macrophages into osteoclasts resulted in their apoptosis. OPG inhibited RAW264.7 macrophage differentiation into osteoclasts, and thereby inhibited the apoptosis of RAW264.7 macrophages. RhoV mediated the apoptosis of RAW264.7 macrophages during osteoclast differentiation.

Objective: To investigate the effect of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) on the proliferation of ovarian carcinoma 3AO cells in vitro and its molecular mechanism., Methods: Ovarian carcinoma 3AO cells were incubated with 12.5, 25.0, 50.0 ng/mL TRAIL proteins for 72 hours, respectively. At 24, 48 and 72 hours, the cells were collected to observe the morphological change under an inverted microscope, detect the cell proliferation using methyl thiazolyl tetrazolium (MTT) assay, the apoptosis rate and cell cycle using flow cytometry (FCM), the morphological features of apoptotic cells using TdT-mediated-dUTP nick end labeling (TUNEL) and the expression of caspase-3 protein using Western blotting., Results: The growth of 3AO cells was inhibited by different concentrations of TRAIL (P<0.05). Morphological change of 3AO cells was clearly observed. TRAIL protein at 25 and 50 ng/mL significantly induced 3AO cell apoptosis and cell cycle arrest. With the treatment time went by, the percentage of cells at G1 phase increased and cells at S and G2/M phase decreased. The expression of caspase-3 protein was raised by TRAIL. No significant differences were noted in the apoptosis rate and the expression of caspase-3 protein between the 25 and 50 ng/mL TRAIL groups (P>0.05)., Conclusion: TRAIL protein could promote the apoptosis of 3AO cells through inhibiting cell growth cycle, blocking DNA synthesis and activating caspase-3.

Intervertebral disc degeneration (IDD) is one of the main causes of low back pain, which affects the patients' quality of life and health and imposes a significant socioeconomic burden. Despite great efforts made by researchers to understand the pathogenesis of IDD, effective strategies for preventing and treating this disease remain very limited. Sirtuins are a highly conserved family of (NAD+)‐dependent deacetylases in mammals that are involved in a variety of metabolic processes in vivo. In recent years, sirtuins have attracted much attention owing to their regulatory roles in IDD on physiological activities such as inflammation, apoptosis, autophagy, aging, oxidative stress, and mitochondrial function. At the same time, many studies have explored the therapeutic effects of sirtuins‐targeting activators or micro‐RNA in IDD. This review summarizes the molecular pathways of sirtuins involved in IDD, and summarizes the therapeutic role of activators or micro‐RNA targeting Sirtuins in IDD, as well as the current limitations and challenges, with a view to provide possible solutions for the treatment of IDD. [ABSTRACT FROM AUTHOR]

Disulfidptosis is a newly discovered form of programmed cell death that is induced by disulfide stress. It is closely associated with various cancers, including head and neck squamous cell carcinoma (HNSCC). However, the factors involved in the modulation of disulfidptosis-related genes (DRGs) still remain unknown. In this study, we established and validated a novel risk score model composed of 11 disulfidptosis-related lncRNAs (DRLs) based on 24 DRGs in HNSCC. The results revealed strong correlations between the 11-DRL prognostic signature and clinicopathological features, immune cell infiltration, immune-related functions, and disulfidptosis-associated pathways, including NADPH and disulfide oxidoreductase activities. Furthermore, we studied and verified the involvement of ALMS1-IT1, one of the 11 model DRLs, in the disulfidptosis of HNSCC cell lines. A series of assays demonstrated that ALMS1-IT1 modulated cell death under starvation conditions in a pentose phosphate pathway (PPP)-dependent manner. Knockdown of ALMS1-IT1 inhibited the PPP, contributing to a decline in NADPH levels, which resulted in the formation of multiple intermolecular disulfide bonds between actin cytoskeleton proteins and the collapse of F-actin in the cytoplasm. Therefore, ALMS1-IT1, which is highly expressed in SLC7A11high cells, can be considered a promising therapeutic target for disulfidptosis-focused treatment strategies for cancer and other diseases. [ABSTRACT FROM AUTHOR]

Mometasone furoate (MF) is a kind of glucocorticoid with extensive pharmacological actions, including inhibiting tumor progression; however, the role of MF in head and neck squamous cell carcinoma (HNSCC) is still unclear. This study aimed to evaluate the inhibitory effect of MF against HNSCC and investigate its underlying mechanisms. Cell viability, colony formation, cell cycle and cell apoptosis were analyzed to explore the effect of MF on HNSCC cells. A xenograft study model was used to investigate the effect of MF on HNSCC in vivo. The core targets of MF for HNSCC were identified using network pharmacology analysis, TCGA database analysis and real-time PCR. Molecular docking was performed to determine the binding energy. Protein tyrosine phosphatase non-receptor type 11 (PTPN11)-overexpressing cells were constructed, and then, the cell viability and the expression levels of proliferation- and apoptosis-related proteins were detected after treatment with MF to explore the role of PTPN11 in the inhibitory effect of MF against HNSCC. After cells were treated with MF, cell viability and the number of colonies were decreased, the cell cycle was arrested and cell apoptosis was increased. The xenograft study results showed that MF could inhibit cell proliferation via promoting cell apoptosis in vivo. PTPN11 was shown to be the core target of MF against HNSCC via network pharmacology analysis, TCGA database analysis and real-time PCR. The molecular docking results revealed that PTPN11 exhibited the strongest ability to bind to MF. Finally, MF could attenuate the effects of increased cell viability and decreased cell apoptosis caused by PTPN11 overexpression, suggesting that MF can inhibit the progression of HNSCC by regulating PTPN11. MF targeted PTPN11, promoting cell cycle arrest and cell apoptosis, and consequently exerting effective anti-tumor activity. [ABSTRACT FROM AUTHOR]

Polybrominated diphenyl ethers (PBDEs) are classic and emerging pollutants that are potentially harmful to the human immune system. Research on their immunotoxicity and mechanisms suggests that they play an important role in the resulting pernicious effects of PBDEs. 2,2′,4,4′-Tetrabrominated biphenyl ether (BDE-47) is the most biotoxic PBDE congener, and, in this study, we evaluated its toxicity toward RAW264.7 cells of mouse macrophages. The results show that exposure to BDE-47 led to a significant decrease in cell viability and a prominent increase in apoptosis. A decrease in mitochondrial membrane potential (MMP) and an increase in cytochrome C release and caspase cascade activation thus demonstrate that cell apoptosis induced by BDE-47 occurs via the mitochondrial pathway. In addition, BDE-47 inhibits phagocytosis in RAW264.7 cells, changes the related immune factor index, and causes immune function damage. Furthermore, we discovered a significant increase in the level of cellular reactive oxygen species (ROS), and the regulation of genes linked to oxidative stress was also demonstrated using transcriptome sequencing. The degree of apoptosis and immune function impairment caused by BDE-47 could be reversed after treatment with the antioxidant NAC and, conversely, exacerbated by treatment with the ROS-inducer BSO. These findings indicate that oxidative damage caused by BDE-47 is a critical event that leads to mitochondrial apoptosis in RAW264.7 macrophages, ultimately resulting in the suppression of immune function. [ABSTRACT FROM AUTHOR]

Ferroptosis is a new type of iron-dependent programmed cell death. In recent years, its role in the diagnosis and treatment of multiple tumors, including non-small cell lung cancer (NSCLC), has been continuously observed. The relationship between the ferroptosis-related genes and the prognosis of patients with NSCLC needs to be clarified. In this study, The Cancer Genome Atlas (TCGA) and the Gene Expression Synthesis database (Gene Expression Omnibus, GEO) were used to build a model of ferroptosis-related differentially expressed genes (DEGs). A total of 101 ferroptosis-related DEGs were screened using R language, and a 12-gene signature was finally established through univariate Cox regression analysis and least absolute shrinkage and selection operator (LASSO)-penalized Cox regression analysis. According to the risk scores, the patients were divided into a high-risk or a low-risk group, with patients in the low-risk group showing better prognosis. AURKA , one of the genes in the 12-gene signature, was found to be highly expressed in tumors. In addition, further study verified AURKA to be a negative regulator of ferroptosis in NSCLC cells. Ophiopogonin B (OP-B) had been reported to induce apoptosis, mitotic catastrophe, and autophagy in NSCLC cells. Herein, proteomic sequencing analysis and OP-B administration revealed the upregulation of AURKA and the downregulation of PHKG2 and SLC7A5 in the 12-gene signature, indicating that OP-B induced ferroptosis in NSCLC. Determination of the concentrations of malondialdehyde (MDA), glutathione (GSH), and intracellular iron and the mitochondrial membrane potential (MMP) confirmed the induction of ferroptosis by OP-B in vitro. Furthermore, transmission electron microscopy (TEM) examination of lung cancer xenotransplantation in nude mice confirmed that OP-B induced ferroptosis in vivo. Further study of the molecular mechanism showed that the ferroptosis effect caused by OP-B can be partially reversed by the overexpression of AURKA. Overall, our study established a new ferroptosis-related risk prediction model for the prognosis of patients with NSCLC, revealed the enrichment pathways of ferroptosis in NSCLC, and discovered the negative regulation of AURKA in ferroptosis. On this basis, we demonstrated that OP-B can induce ferroptosis in NSCLC and clarified the specific molecular mechanism of OP-B inducing ferroptosis by regulating the expression of AURKA. [ABSTRACT FROM AUTHOR]

C1q/tumor necrosis factor-related protein 13 (CTRP13) has been reported to participate in cardiovascular diseases. However, the role and molecular mechanism of CTRP13 in obesity-induced endothelial cell damage is still unclear. In palmitic acid (PA)-induced human umbilical vein endothelial cells (HUVECs), qRT-PCR and western blot were used to examine CTRP13 expression. CCK-8 and TUNEL assays were adopted to assess cell viability and apoptosis, respectively. ROS level and MDA content were evaluated by their commercial kits and inflammatory cytokines were measured using ELISA. Endothelial cell dysfunction was evaluated by detecting NO production and eNOS expression, and tube formation assay was performed to assess angiogenesis. AMPK pathway-related proteins were detected by western blot. The results showed that CTRP13 was downregulated in PA-induced HUVECs. CTRP13 overexpression reduced PA-induced cell viability loss and oxidative stress in HUVECs. Moreover, CTRP13 overexpression suppressed PA-induced inflammation and apoptosis, improved angiogenesis ability, and alleviated endothelial cell dysfunction in HUVECs. In addition, CTRP13 overexpression activated AMPK pathway and regulated the expressions of downstream NOX1/p38 and KLF2. Furthermore, compound C countervailed the impacts of CTRP13 overexpression on cell viability, oxidative stress, inflammation, apoptosis and endothelial function in PA-induced HUVECs. To sum up, CTRP13 overexpression may alleviate PA-induced endothelial cell damage. • CTRP13 was downregulated in palmitic acid-induced HUVECs. • CTRP13 alleviated PA-induced endothelial cell inflammation, apoptosis, and dysfunction. • Compound C abolishes the protective role of CTRP13 against PA-induced endothelial cell injury. [ABSTRACT FROM AUTHOR]

The rhizome of Curcuma wenyujin Y.H. Chen & C. Ling, also known as Wen-E-Zhu, has been used for cancer treatment since ancient times, with roots dating back to the Song Dynasty. Elemene (EE), a sesquiterpene extract with potent anticancer properties, is extracted from Wen-E-Zhu, with β-elemene (BE) being its main active compound, along with trace amounts of β-caryophyllene (BC), γ-elemene and δ-elemene isomers. EE has demonstrated broad-spectrum anti-cancer effects and is commonly used in clinical treatments for various types of malignant cancers, including lung cancer. Studies have shown that EE can arrest the cell cycle, inhibit cancer cell proliferation, and induce apoptosis and autophagy. However, the exact mechanism of its anti-lung cancer activity remains unclear and requires further research and investigation. In this study, the possible mechanism of EE and its main active components, BE and BC, against lung adenocarcinoma was investigated by using A549 and PC9 cell lines. The subcutaneous tumor model of nude mice was constructed to evaluate the efficacy of EE in vivo , then the in vitro half-inhibitory concentration (IC 50) of EE and its main active components, BE and BC, on A549 and PC9 cells at different concentrations were determined by CCK-8. Flow cytometry was used to detect the apoptosis and cycle of A549 and PC9 cells treated with different concentrations of BE and BC for 24 h. Non-targeted metabolomics analysis was performed on A549 cells to explore potential target pathways, which were subsequently verified through kit detection and western blot analysis. Injection of EE in A549 tumor-bearing mice effectively suppressed cancer growth in vivo. The IC 50 of EE and its main active components, BE and BC, was around 60 μg/mL. Flow cytometry analysis showed that BE and BC blocked the G 2 /M and S phases of lung adenocarcinoma cells and induced apoptosis, leading to a significant reduction in mitochondrial membrane potential (MMP). Results from non-targeted metabolomics analysis indicated that the glutathione metabolism pathway in A549 cells was altered after treatment with the active components. Kit detection revealed a decrease in glutathione (GSH) levels and an increase in the levels of oxidized glutathione (GSSG) and reactive oxygen (ROS). Supplementation of GSH reduced the inhibitory activity of the active components on lung cancer and also decreased the ROS content of cells. Analysis of glutathione synthesis-related proteins showed a decrease in the expression of glutaminase, cystine/glutamate reverse transporter (SLC7A11), and glutathione synthase (GS), while the expression of glutamate cysteine ligase modified subunit (GCLM) was increased. In the apoptosis-related pathway, Bax protein and cleaved caspase-9/caspase-9 ratio were up-regulated and Bcl-2 protein was down-regulated. EE, BE, and BC showed significant inhibitory effects on the growth of lung adenocarcinoma cells, and the mechanism of action was linked to the glutathione system. By down-regulating the expression of proteins related to GSH synthesis, EE and its main active components BE and BC disrupted the cellular redox system and thereby promoted cell apoptosis. [Display omitted] • Non-targeted metabonomics revealed elemene's potential pathways against lung cancer cells. • Elemene reduces GSH content and GSH/GSSG ratio in lung cancer cells. • Elemene downregulates glutaminase, SLC7A11, and GS to decrease GSH synthesis. [ABSTRACT FROM AUTHOR]

Diisononyl phthalate (DINP), a mixture of chemical compounds composed of diverse isononyl esters of phthalic acid, is commonly applied as a plasticizer to substitute for di (2-ethylhexyl) phthalate (DEHP). It has been demonstrated that DINP exposure impairs the functions of kidney and liver in animals. However, the effects and potential mechanisms of DINP exposure on the female reproduction, especially the oocyte quality are still poorly understood. Here, we discovered that DINP exposure weakened the porcine oocyte meiotic competency (78.9% vs 53.6%, P < 0.001) and fertilization ability (78.5% vs 34.1%, P < 0.0001) during in vitro maturation. Specifically, DINP exposure induced the persistent spindle assembly checkpoint (SAC) activation caused by the disorganized spindle/chromosome apparatus (spindle: 20.0% vs 83.3%, P < 0.001; chromosome: 20.0% vs 80.0%, P < 0.01) to arrest meiotic progression of oocytes at metaphase I stage. In addition, DINP exposure disturbed the dynamics of sperm binding (146.7 vs 58.6, P < 0.0001) and fusion proteins (19.5 vs 11.6, P < 0.0001) in oocytes to compromise their fertilization ability. In particular, transcriptome data uncovered that the action mechanism of DINP on the oocyte maturation was associated with oxidative phosphorylation, apoptosis and autophagy pathways. Lastly, we validated that DINP exposure resulted in the mitochondrial dysfunction (27.2 vs 19.8, P < 0.0001) and elevated levels of reactive oxygen species (ROS; 8.9 vs 19.9, P < 0.0001) to trigger the occurrence of apoptosis (7.2 vs 13.1, P < 0.0001) and protective autophagy (68.6 vs 139.3, P < 0.01). Altogether, our findings not only testify that DINP has a potentially adverse impact on the mammalian oocyte quality, but also provide a scientific reference regarding how environment pollutants act on the female germ cell development. [Display omitted] • DINP exposure impedes both nuclear and cytoplasmic maturation of porcine oocytes. • DINP exposure disturbs the cytoskeleton organization and mitochondrial dynamics. • DINP exposure leads to the defects in the fertilization ability. • DINP exposure produces the excessive ROS to induce the apoptosis in porcine oocytes. [ABSTRACT FROM AUTHOR]

Beta-B2-crystallin (CRYBB2), encoded by Crybb2 gene, is a major protein in the mammalian eye lens that plays an important role in maintaining the transparency of the ocular lens. However, CRYBB2 also plays important roles in many extra-lenticular tissues and organs such as the retina, brain and testis. Our previous studies demonstrated that male Crybb2 deficient ( Crybb2 −/− ) mice have reduced fertility compared with wild-type (WT) mice, while female Crybb2 −/− mice exhibited reduced ovary weights and shorter estrous cycle percentages. Here we specifically investigated the role of CRYBB2 in the female reproductive system. Our studies revealed that ovaries from female Crybb2 −/− mice exhibited significantly reduced numbers of primordial, secondary and pre-ovulatory follicles when compared with WT mice, while the rate of atretic follicles was also increased. Additionally, fewer eggs were collected from the oviduct of Crybb2 −/− female mice after superovulation. Estrogen levels were higher in the metestrus and diestrus cycles of female Crybb2 −/− mice, while progesterone levels were lower in diestrus cycles. Furthermore, the expression of survival and cell cycle genes, Bcl-2 , Cdk4 and Ccnd2 , were significantly decreased in granulosa cells isolated from female Crybb2 −/− mice, consistent with the predominant expression of CRYBB2 in ovarian granulosa cells. Our results reveal a critical role for CRYBB2 in female fertility and specific effects on the proliferation and survival status of ovarian granulosa cells. [ABSTRACT FROM AUTHOR]

Perfluorooctane sulfonate (PFOS) is a widely used artificial surfactant with potential toxicity to humans and animals. However, little is known about the impact of PFOS on the female germ cell development. Here, we report that PFOS exposure weakens oocyte quality by disturbing oocyte meiotic competency and fertilization ability. Specifically, PFOS exposure impaired cytoskeleton assembly including spindle organization and actin polymerization to cause the oocyte maturation arrest. In addition, PFOS exposure also impaired the mitochondrial dynamics and function, resulting in the increased levels of reactive oxygen species (ROS) and DNA damage as well as generation of apoptosis. Lastly, PFOS exposure compromised the distribution of cortical granules (CGs) and their component ovastacin, leading to the failure of sperm binding and fertilization. Altogether, our study illustrates that oxidative stress-induced apoptosis is a major cause for the deteriorated quality of porcine oocytes exposed to PFOS. [Display omitted] • PFOS exposure impairs the oocyte meiotic progression and competency. • PFOS exposure compromises the sperm binding ability and fertilization capacity of oocytes. • PFOS exposure produces excessive ROS to induce the apoptosis in oocytes. [ABSTRACT FROM AUTHOR]

Berberine (BBR) has a neuroprotective effect against ischemic stroke, but its specific protective mechanism has not been clearly elaborated. This study explored the effect of BBR on the canopy FGF signaling regulator 2 (CNPY2) signaling pathway in the ischemic penumbra of rats. The model of cerebral ischemia-reperfusion injury (CIRI) was established by the thread embolization method, and BBR was gastrically perfused for 48 h or 24 h before operation and 6 h after operation. The rats were randomly divided into four groups: the Sham group, BBR group, CIRI group, and CIRI + BBR group. After 2 h of ischemia, followed by 24 h of reperfusion, we confirmed the neurologic dysfunction and apoptosis induced by CIRI in rats (p < 0.05). In the ischemic penumbra, the expression levels of CNPY2-regulated endoplasmic reticulum stress-induced apoptosis proteins (CNPY2, glucose-regulated protein 78 (GRP78), double-stranded RNA-activated protein kinase-like ER kinase (PERK), C/EBP homologous protein (CHOP), and Caspase-3) were significantly increased, but these levels were decreased after BBR treatment (p < 0.05). To further verify the inhibitory effect of BBR on CIRI-induced neuronal apoptosis, we added an endoplasmic reticulum-specific agonist and a PERK inhibitor to the treatment. BBR was shown to significantly inhibit the expression of apoptotic proteins induced by endoplasmic reticulum stress agonist, while the PERK inhibitor partially reversed the ability of BBR to inhibit apoptotic protein (p < 0.05). These results confirm that berberine may inhibit CIRI-induced neuronal apoptosis by downregulating the CNPY2 signaling pathway, thereby exerting a neuroprotective effect. [ABSTRACT FROM AUTHOR]

The cancer testis antigen sperm protein 17 (Sp17) is a promising antigenic target in epithelial ovarian cancer (EOC) vaccine development. However, its role in ovarian cancer is unclear. We isolated and expanded Sp17+ and Sp17− clones from the murine EOC cell line ID8, and compared their in-vitro cell growth characteristics and in-vivo tumorigenicity. We also examined the potential co-expression of molecules that may influence cancer cell survival and interaction with immune cells. These include stimulatory and immunosuppressive molecules, such as major histocompatibility class I molecules (MHC I), MHC II, cytotoxic T lymphocyte associated antigen-4 (CTLA-4), CD73, CD39, tumor necrosis factor receptor II (TNFRII), signal transducer and activator of transcription 3 (STAT3) and programmed death-ligand 1 (PD-L1). Whilst the presence of Sp17 was not correlated with the ID8 cell proliferation/growth capacity in vitro, it was critical to enable progressive tumor formation in vivo. Flow cytometry revealed that Sp17+ ID8 cells displayed higher expression of both STAT3 and PD-L1, whilst MHC II expression was lower. Moreover, Sp17high (PD-L1+MHCII−) cell populations showed significantly enhanced resistance to Paclitaxel-induced cell death in vitro compared to Sp17low (PD-L1−MHCII+) cells, which was associated in turn with increased STAT3 expression. Together, the data support Sp17 as a factor associated with in-vivo tumor progression and chemo-resistance, validating it as a suitable target for vaccine development. [ABSTRACT FROM AUTHOR]

[Display omitted] Immune checkpoint blockade (ICB) therapy, represented by programmed cell death protein 1 (PD-1) and its ligand (PD-L1) monoclonal antibodies (mAbs), has shown an obvious benefit for melanoma immunotherapy, but the overall response rate is still low. To find an effective combination therapy strategy, we successfully produced small size silver nanoparticles coated with sucrose (S-AgNPs) as potent adjuvants. The antitumor effects of S-AgNPs were tested in vitro and comparatively investigated in immunodeficient and immunocompetent mice with melanoma. Fluorescence-activated cell sorting and immunofluorescent staining analysis were conducted to identify the tumor microenvironments. The expression of PD-L1 in tumors was tested by multiple methods. The combination therapy and potential toxicity of S-AgNPs and PD-1 mAbs were assessed in melanoma-bearing mice. In our findings, S-AgNPs presented potent antitumor effects, good druggability and low systemic toxicity. Functionally, we found that S-AgNPs exhibited better antitumor effects in immunocompetent mice. Mechanistically, we showed that S-AgNPs suppress tumor cell proliferation by inducing cellular apoptosis and promote cytotoxic CD8+ T cell infiltration and activity. Preclinically, S-AgNPs showed excellent local antitumor activity and mild systemic immunotoxicity with PD-1 mAbs in the inhibition of melanoma proliferation, providing a novel clinical combination treatment strategy. [ABSTRACT FROM AUTHOR]

Herbal medicines (HMs) often exert integration effects, including synergistic, additive and antagonistic effects, in such ways that they act on multiple targets and multiple pathways on account of their multiple components. Turmeric, made from the rhizome of Curcuma longa L., is a well-known HM prescribed in the polyherbal formulas for cancer treatment in traditional Chinese medicines (TCMs). However, neither the multiple anticancer compounds of turmeric nor the integration effects of these components are fully known. This work aims to develop a systematic approach to reveal the integration effect mechanisms of multiple anticancer compounds in turmeric against prostate cancer PC3 cells. Combination index and omics technologies were applied to profile the integration effect mechanisms of bioactive compounds in proportions naturally found in turmeric. PC3 cell line (a prostate cancer cell line) fishing and high resolution mass spectrometry were employed to screen and identify the anticancer compounds from turmeric. The combinations which contain different cell-bound compounds in natural proportions were prepared for further evaluation of anti-cancer activity by using cell viability assays, and assessment of cell apoptosis and cell cycle analysis. Combination index analysis was applied to study the integration effects of the anticancer compounds in their natural proportions. Finally, quantitative glycoproteomics/proteomics and Western blot were implemented to reveal the potential synergistic effect mechanisms of the anticancer compounds based on their natural proportions in turmeric. Three curcuminoids (curcumin, CUR; demethoxycurcumin, DMC; bisdemethoxycurcumin, BDMC) in turmeric were discovered and shown to possess significant synergistic anticancer activities. Combination index analysis revealed an additive effect of CUR combined with DMC or BDMC and a slight synergistic effect of DMC combined with BDMC in natural proportions in turmeric, while a combination of all three curcuminoids (CUR, DMC and BDMC) at a ratio of 1:1:1 yielded superior synergistic effects. Interestingly, the presence of BDMC and DMC are essential for synergistic effect. Glycoproteomics and proteomics demonstrated that different curcuminoids regulate various protein pathways, such as ribosome, glycolysis/gluconeogenesis, biosynthesis of amino acids, and combination of CUR + DMC + BDMC showed the most powerful effects on down-regulation of protein expression. Our analytical approach provides a systematic understanding of the holistic activity and integration effects of the anti-cancer compounds in turmeric and three curcuminoids of turmeric showed a synergistic effect on PC3 cells. Image 1 • A combination index and glycoproteomics-based approach was proposed for integration effects profiling of curcuminoids. • Three curcuminoids in turmeric were proved to possess significant synergetic anticancer activities against PC3 cells. • BDMC and DMC are essential for these active compounds to obtain the synergistic effect against PC3 cells. • The combination of CUR + DMC + BDMC showed the most powerful on down-regulation of the protein expression. [ABSTRACT FROM AUTHOR]